Hepatitis B virus (HBV) is a major cause of serious liver diseases, including chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC) throughout the world and the US, especially among minorities including African Americans, Native Americans, and Asian Americans. Yet, the molecular mechanisms of carcinogenesis in chronic hepatitis B are unclear. In particular, it has not been convincingly shown in the literature that HBV itself is carcinogenic. Recent clinical data have pointed to an association between HCC and HBV mutants with in-frame deletions in the preS2 region of the surface gene that cause stress in the endoplasmic reticulum. We have generated transgenic mice containing a preS2 mutant HBV genome, and found that these mice develop HCC. This is the first direct demonstration of carcinogenesis induced by HBV in a transgenic mouse model using the entire HBV genome that is clinically relevant, and thus these mice represent the only model that is directly relevant to human HBV-associated HCC. We hypothesize that preS2 mutant HBV genomes play an important role in human HBV-associated carcinogenesis, by inducing stress in the endoplasmic reticulum, followed by oxidative stress, mitochondrial damage, and nuclear DMA damage. We will test this hypothesis with three specific aims. 1) We will characterize the neoplasms in these transgenic mice in terms of genomic instability, genetic loci with amplifications or deletions, and beta-catenin mutations, and compare the results with published data on human HCC caused by HBV. 2) We will determine if oxidative stress, mitochondrial damage, and nuclear DMA damage can be detected in our transgenic mice and in human livers infected with preS2 mutants;3) We will determine if treatment of these mice with antioxidants will reduce the incidence of HCC. It is anticipated that these experiments will provide direct evidence on the role of preS2 mutants in HCC formation, begin to elucidate the molecular mechanisms of carcinogenesis during HBV infection, and lead in the future to the identification of molecular targets for the prevention and/or therapy of HCC. Hepatitis B virus is a major cause of suffering and death in the world, by causing liver injury, cirrhosis (liver scarring) and liver cancer. It causes more than 1.2 million deaths annually. Current treatment for hepatitis B is expensive and inadequate, and liver cancer has an extremely low cure rate. We hope that our research can lead to the development of new ways to prevent, detect, and/or treat liver cancer in these patients.